Interrogation of a live-attenuated enterotoxigenic Escherichia coli vaccine highlights features unique to wild-type infection
PublisherNature Publishing Group
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AbstractEnterotoxigenic Escherichia coli (ETEC) infections are a common cause of severe diarrheal illness in low- and middle-income countries. The live-attenuated ACE527 ETEC vaccine, adjuvanted with double mutant heat-labile toxin (dmLT), affords clear but partial protection against ETEC challenge in human volunteers. Comparatively, initial wild-type ETEC challenge completely protects against severe diarrhea on homologous re-challenge. To investigate determinants of protection, vaccine antigen content was compared to wild-type ETEC, and proteome microarrays were used to assess immune responses following vaccination and ETEC challenge. Although molecular interrogation of the vaccine confirmed expression of targeted canonical antigens, relative to wild-type ETEC, vaccine strains were deficient in production of flagellar antigens, immotile, and lacked production of the EtpA adhesin. Similarly, vaccination ± dmLT elicited responses to targeted canonical antigens, but relative to wild-type challenge, vaccine responses to some potentially protective non-canonical antigens including EtpA and the YghJ metalloprotease were diminished or absent. These studies highlight important differences in vaccine and wild-type ETEC antigen content and call attention to distinct immunologic signatures that could inform investigation of correlates of protection, and guide vaccine antigen selection for these pathogens of global importance. Copyright 2019, The Author(s).
SponsorsResearch reported in this publication was supported by PATH; funding from National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health (NIH) under Award Numbers R01AI089894, R01AI126887 (jmf), the Washington University Institute of Clinical and Translational Sciences grant UL1 TR000448 from the National Center for Advancing Translational Sciences (NCATS) of the NIH, and the Department of Veterans Affairs (5I01BX001469, jmf). The mass spectrometric experiments were designed and performed at the Washington University Proteomics Shared Resource (WU-PSR), R. Reid Townsend MD.PhD., Director. The WU-PSR is supported in part by the WU Institute of Clinical and Translational Sciences (NCATS UL1 TR002345), the Mass Spectrometry Research Resource (NIGMS P41 GM103422) and the Siteman Comprehensive Cancer Center Support Grant (NCI P30 CA091842). The expert technical assistance of Jim Malone, Dr. Yiling Mi and Rose Connors is gratefully acknowledged. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH, NIAID, NCATS, the Department of Veterans Affairs, or PATH. The authors thank Edwin Oaks (Walter Reed Army Institute of Research), Stephen Savarino, and Stephen Poole (Naval Medical Research Center) for providing select purified antigens that were used in production of the arrays.
Identifier to cite or link to this itemhttps://www.scopus.com/inward/record.uri?eid=2-s2.0-85071607105&doi=10.1038%2fs41541-019-0131-7&partnerID=40&md5=40ed948af6dd5a9173b13938e7b3e862; http://hdl.handle.net/10713/10826